Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, and may be broadly classified into tyrosine or serine/threonine kinases based on the amino acids phosphorylated. This covalent post-translational modification is a pivotal component of normal cellular communication and maintenance of homeostasis. Tyrosine kinase signaling pathways normally prevent deregulated proliferation or contribute to sensitivity towards apoptotic stimuli. These signaling pathways are often genetically or epigenetically altered in cancer cells to impart a selection advantage to the cancer cells. Understandably therefore, aberrant enhanced signaling emanating from tyrosine kinase endows these enzymes a dominating oncoprotein status, resulting in the malfunctioning of the signaling network. Inappropriate kinase activity arising from mutation, over-expression, or inappropriate regulation, dys-regulation, mis-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited too cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease, and to various blinding ocular diseases.
Transmembrane receptor protein kinases exhibit an extracellular domain, capable of ligand binding. These ligand binding mechanisms trigger activation of the kinase catalytic domain which initiates a cascade of signals that controls intracellular functions. Examples of receptor protein kinase are growth factors such as EGF, FGF, VEGF, PDGF and IGF. Nonreceptor protein kinases can be found in many compartments of a cell from inner-cell surface membranes to the cell nucleus.
Several families of tyrosine kinases can function in each of the responses to various stimuli and pathways, and biological cellular responses relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility. Additional complexity results from extensive cross-talk between different receptor kinase pathways. One family of cytoplasmic tyrosine kinases capable of communicating with a large number of different receptors is the Src protein tyrosine kinase family. The c-Src proto-oncogene can play a role in the development, growth, progression, and metastasis of a wide variety of human cancers. Src over-activation, in the form of elevated kinase activity and protein expression levels, has been demonstrated in several major cancer types, including colon, breast, pancreatic, lung, and brain carcinomas. Src kinase modulates signal transduction through multiple oncogenic pathways, including EGFR, Her2/neu, PDGFR, FGFR, and VEGFR. There are structural and functional interactions between the Src family kinases and cellular receptors, and from Src family kinases on receptor-induced biological activities regulated by these kinases.
There is a body of evidence linking kinase mis-regulation, dysregulation and mutation to a variety of oncological indications. Kinases have been implicated in ocular diseases, not limited to, but including age related macular degeneration, diabetic macular edema and proliferative diabetic retinopathy.
Biochemically, cellular stimuli that lead to Src activation result in increased association between Src and the cytoskeleton. As a result, Src mediates the phosphorylation of many intracellular substrates such as EGFR, FAK, PYK2, paxillin, Stat3, and cyclin D. The biological effects of these interactions affect cell motility, adhesion, cell cycle progression, and apoptosis and might have some connection to the disease related effects stated above. Thus, Src plays a role in responses to regional hypoxia, limited nutrients, and internal cellular effects to self-destruct.
Increased c-Src TK activity results in breakdown of the E-cadherin-mediated epithelial cell-cell adhesion, which can be restored by Src inhibition. Intimate connections between increased VEGF activity, Src activity, and cellular barrier function related to vascular leak have been also demonstrated. Inhibition of Src results in decrease in vascular leak when exogenous VEGF is administered in in vivo studies. Examples where excessive vascular permeability leads to particularly deleterious effects include pulmonary edema, cerebral edema, and cardiac edema.
Since the activation and perhaps over-expression of Src has been implicated in cancer, osteoporosis, stroke, myocardial infarction, and vascular leak, among others, a small molecule inhibitor of c-Src can be beneficial for the treatment of several disease states. VEGFR inhibition has been shown to be validated for disease states involving angiogenesis, various cancers and in back of the eye diseases as exemplified by acute macular degeneration (AMD), diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), all blinding eye diseases that afflicts large numbers of people. Dual Src and VEGFR inhibitors thus have the potential for multiple utility in several different disease states.